More than 40,000 people die from breast cancer each year, but many of those deaths are caused by the original cancer spreading to secondary locations. A common site for breast cancer to spread, or metastasize, to is bone, and once it has, the cancer becomes much more difficult to detect and treat. To study why breast cancer preferentially metastasizes to bone, Notre Dame researchers at the Harper Cancer Research Institute (HCRI) are evaluating the relationship between the two by using breast cancer cells and human bone.

This work is led by Laurie Littlepage, Campbell Family Assistant Professor of Cancer Research in the department of chemistry and biochemistry, and Glen Niebur, professor of aerospace and mechanical engineering and director of the Tissue Mechanics Laboratory at the University of Notre Dame. Niebur’s experience with osteoporosis and bone makes his collaboration with Littlepage, a breast cancer researcher, particularly beneficial and synergistic. Together with Dr. Stephen F. Mitros and Dr. Mark Walsh of Memorial Hospital of South Bend, this team is able to conduct their research by utilizing human bone donated by patients receiving hip replacements that would otherwise have been discarded.

Laurie Littlepage and Glen Niebur examine bone at the Harper Cancer Research Institute.

“The Harper Cancer Research Institute is distinctive in a number of ways when it comes to conducting its research collaborations,” said M. Sharon Stack, Ann F. Dunne and Elizabeth Riley Director of the HCRI and Kleiderer-Pezold Professor of Chemistry and Biochemistry. “One is that we are proud to have a number of engineers, like Niebur, working with scientists on cancer research. Another is that we greatly benefit from our partnership with Memorial Hospital, which is recognized nationally for providing a high level of cancer care, trauma care, and surgical care, as well as being a leader in innovation."

"Notre Dame’s collaboration with Memorial Hospital is imperative to not only this study by Littlepage and Niebur, but also to several other research efforts at the institute and beyond." — M. Sharon Stack, director of the Harper Cancer Research Institute

As local patients have their routine hip replacement surgeries, they can opt to anonymously donate their removed bone. After the surgery, the tissue is then placed in a sterile container and transported directly to the Tissue Mechanics Laboratory. Once delivered to the lab, the bone is carefully prepared so that it can be used to study its interaction with breast cancer cells.

Glen Niebur advises graduate student Kimberly Curtis.

During the experiments, the bone tissue is kept alive by feeding it with a cell culture medium, which contains glucose and essential vitamins and nutrients. Theoretically, if no infection occurs, the bone cultures could grow and remain alive indefinitely. Niebur developed this bone culture technique with collaborators at the Regenerative Medicine Institute (REMEDI) in the National University of Ireland, Galway, and his laboratory is the first to adapt it to study cancer metastasis.

The research team’s ability to maintain the bone in culture media with cancer cells is important for the success of this study. To explain, Niebur said, “Although there are other models that are applied every day by scientists for cancer research, we know they are less representative of human tissue and not nearly as similar to human genetics as researchers would like them to be. "

"By working with human bone, we have an opportunity to more accurately account for biological diversity and know our work is likely more applicable to breast cancer metastasis patients." — Glen Niebur, professor of aerospace and mechanical engineering

One of the goals of the study is to decipher what cell type in bone or bone marrow attracts the breast cancer cells. Their first step is to conduct experiments to determine what exactly the cancer cells are attracted to. For this, the research team took human bone with marrow and human bone without marrow and compared how quickly breast cancer cells moved to either option. Although still early on in the study, so far they have observed that the breast cancer cells move significantly faster towards the bone with marrow. This potentially means that a cell type in the marrow, rather than the bone itself, could be more attractive to the cancer cells.

Ricardo Romero Moreno works with adviser Laurie Littlepage in her lab.

The researchers are also considering what role bone itself plays in breast cancer cell dormancy, which is the stage in cancer progression where cells cease to divide but still survive and wait until there is an appropriate environmental condition to proliferate. Currently, it is unknown what makes a dormant breast cancer cell begin to proliferate after a period of time. So, in addition to conducting experiments on which bone the cancer cells move fastest, the researchers are also looking at whether or not those cells will proliferate once they arrive or if they will lay dormant.

“We know that some patients develop metastatic tumors years after their cancer was treated. This suggests that some breast cancer cells remain dormant for extended periods of time. We want to determine if the bone microenvironment promotes this cancer cell dormancy, as well as to identify the factors that cause the dormant cells to begin to proliferate and develop into a metastatic tumor,” said Littlepage.

In addition to human bone, mouse bone is also used in the research.

A significant part of this study is to consider which of a bone’s many physical and biological characteristics may be factors in promoting cancer cell dormancy. For example, bone serves a structural function, in that it upholds the body and allows for movement. The bone also protects bone marrow residing within the bone’s cavities, which could be an optimal place for the cancer cells to reside in a dormant state. Narrowing down the roles of the factors involved could help researchers understand how breast cancer cell dormancy is regulated in the bone.

“At this point, we do not have a full understanding of whether or not the cavities filled with bone marrow provide an especially hospitable residence for cancer cells due to the mechanical properties or signaling from the surrounding cells,” said Niebur. “One of the aims of this research is to evaluate if these factor into the initial dormancy and whether normal bone function – like the loading on bones from daily activities – has an impact on triggering proliferation or maintaining a dormant state. Throughout this study, our goal is to better determine how the integrated bone environment affects the state of the disseminated cancer cells.”

Littlepage and Niebur are both affiliated members of the HCRI and are using breast cancer cells, human bone, and animal bone to complete the study. Others collaborators include Ricardo Romero Moreno, graduate student of the integrated biomedical sciences graduate program in the Littlepage lab, Kimberly Curtis, graduate student of the bioengineering program in the Niebur lab, and Joseph Dynako and David Zimmer, medical students at the Indiana University School of Medicine-South Bend in partnership with the University of Notre Dame at Memorial Hospital of South Bend. Littlepage is also an affiliate of Advanced Diagnostics and Therapeutics.

To learn more about cancer research at the University of Notre Dame, please visit harpercancer.nd.edu.

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About

Investigators in the Harper Cancer Research Institute are dedicated to conducting innovative and integrative research that confronts the complex challenges of cancer. From common malignancies to rare and recalcitrant cancers, researchers at the University of Notre Dame and Indiana University School of Medicine-South Bend are united in multi-disciplinary teams with a common goal: to increase the survival of all patients diagnosed with cancer.

The University of Notre Dame is a private research and teaching university inspired by its Catholic mission. Located in South Bend, Indiana, its researchers are advancing human understanding through research, scholarship, education, and creative endeavor in order to be a repository for knowledge and a powerful means for doing good in the world. For more information, please see research.nd.edu or @UNDResearch.